Early Rhythm Control in Atrial Fibrillation: Reconciling Trial Populations with Clinic Populations

Abstract

EAST-AFNET 4 established that starting rhythm control -- antiarrhythmic drugs or ablation -- within a year of an atrial
fibrillation diagnosis reduces the composite risk of cardiovascular death, stroke, and hospitalisation for heart failure or acute
coronary syndrome, in a trial of 2,789 patients with early AF plus cardiovascular risk factors (hazard ratio 0.79). A natural
objection to any trial result is that the patients enrolled do not resemble the patients seen in an ordinary clinic. A UK Biobank
analysis addressed this directly and found the objection largely does not hold: 80.9% of participants with incident atrial
fibrillation would have met EAST-AFNET 4's eligibility criteria, and eligible patients experienced a similar treatment benefit
(hazard ratio 0.82) to the trial itself. But a separate real-world analysis of two large cohorts -- 109,739 US claims patients and
11,625 UK Biobank patients -- stratified by comorbidity burden found something more specific: a statistically significant
benefit of early rhythm control appeared only in patients with a higher comorbidity burden (CHA2DS2-VASc ≥4), not in
patients with a lower burden (CHA2DS2-VASc 2-3), in both cohorts independently. This review sets out the trial result, the
generalizability finding that broadly supports it, and the comorbidity-stratified finding that narrows it: eligibility for early
rhythm control is broad, but the population in whom a real-world benefit signal has actually been demonstrated is narrower
than eligibility alone would suggest.